Does Concentration Affect Side Effects When Total Dose Is Constant?
For testosterone topical cream, using different concentrations with the same total dose does NOT meaningfully alter the side-effect profile, because systemic absorption and resulting serum testosterone levels—not the concentration applied—determine adverse effects. However, higher-concentration formulations applied to smaller surface areas may reduce the risk of secondary transfer to others, which is a critical safety consideration distinct from patient-specific side effects. 1
Pharmacokinetic Rationale
Systemic exposure drives side effects, not the concentration of the vehicle. When the same total milligram dose of testosterone is delivered transdermally, the resulting serum testosterone, DHT, and estradiol concentrations are equivalent regardless of whether a higher concentration is applied to a smaller area or a lower concentration to a larger area. 2
Absorption kinetics are dose-dependent, not concentration-dependent. Studies of scrotal testosterone cream demonstrate that peak serum testosterone levels correlate with the total milligram dose administered (12.5 mg, 25 mg, 50 mg), not with the concentration of the formulation. 2
Approximately 60% of applied testosterone remains on intact skin for up to 8 hours after application, regardless of concentration, until the site is washed. 3
Patient-Specific Side Effects (Systemic)
Erythrocytosis
Transdermal testosterone formulations carry a significantly lower risk of erythrocytosis compared with injectable preparations (15.4% vs. 43.8%), but this difference is driven by the route of administration and resulting pharmacokinetic profile—not by the concentration of the topical product. 4, 5
Dose-dependent erythrocytosis risk exists for transdermal testosterone: 2.8% incidence at 5 mg/day delivered, increasing to 11.3% at 50 mg gel (5 mg/day delivered) and 17.9% at 100 mg gel (10 mg/day delivered). 6 This relationship is based on total daily dose, not concentration.
Hematocrit should be monitored periodically; treatment should be withheld if hematocrit exceeds 54%. 5, 6
Cardiovascular and Metabolic Effects
Physiologic replacement doses of transdermal testosterone have minimal effects on lipid profiles, with no consistent changes in HDL, LDL, or total cholesterol across controlled studies. 4
Supraphysiologic testosterone levels—not concentration per se—increase the risk of adverse cardiovascular effects. Only the highest doses (well into the supraphysiologic range) were associated with significant HDL reduction. 4
Androgenic Side Effects
Acne, oily skin, and local skin reactions occur in approximately 5% of gel users, a rate far lower than the 66% skin-reaction rate seen with testosterone patches. 6 These reactions are related to the vehicle and application site, not the concentration of testosterone in the formulation.
Gynecomastia, fluid retention, and benign prostatic hyperplasia are potential side effects of testosterone therapy but are driven by systemic testosterone and estradiol levels, not by the concentration of the topical preparation. 4, 1
Secondary Exposure Risk (Critical Safety Distinction)
Transfer to Partners and Children
Higher-concentration formulations applied to smaller surface areas reduce the risk of secondary transfer because less skin surface is exposed and can be more easily covered with clothing. 1
Virilization has been reported in children secondarily exposed to testosterone gel, including early puberty and genital enlargement. 1
The FDA mandates a boxed warning for all testosterone gels regarding secondary exposure risk. Patients must wash hands immediately after application, cover the application site with clothing after the gel dries, and wash the site thoroughly with soap and water before any anticipated skin-to-skin contact. 1
After 8 hours, approximately 60% of applied testosterone remains on unwashed skin, creating a persistent transfer risk. Washing the skin with water reduces recoverable testosterone to approximately 14%. 3
No increase in serum testosterone was detected in volunteers after intense skin contact with a treated subject, suggesting that transfer risk is low when proper precautions are followed. However, this study involved adult males with suppressed endogenous testosterone, not children or women, who are at higher risk for virilization. 3
Application Site and Concentration Considerations
FDA-Approved Application Sites
Testosterone gel 1.62% is FDA-approved for application to the shoulders and upper arms only. Application to the abdomen, genitals, chest, armpits, or knees is not approved and may alter absorption. 1
Scrotal application is not FDA-approved but produces markedly higher absorption with peak serum testosterone levels of 1204.7 ng/dL within 2 hours using a much lower dose (25 mg) compared with non-scrotal sites. 7, 2 This route is associated with a disproportionate increase in DHT (peak 1.2 ng/mL at 4.9 hours), which may increase androgenic side effects. 2
Concentration and Dosing
Testosterone gel 1.62% delivers 20.25 mg testosterone per pump actuation or packet, with a starting dose of 40.5 mg (2 actuations or 1 packet) applied once daily. 1
Testosterone gel 1% delivers 25 mg testosterone per 2.5 g packet, with a typical dose range of 50–100 mg daily. 6
These formulations are NOT interchangeable because the 1.62% formulation delivers more testosterone per gram of gel than the 1% formulation, requiring different dosing. 6
Monitoring and Dose Adjustment
Serum testosterone levels should be measured 2–3 months after treatment initiation or any dose change, targeting mid-normal values (450–600 ng/dL). 5, 6, 1
Once stable levels are achieved, monitoring every 6–12 months is sufficient. 5, 6
Hematocrit, PSA (in men > 40 years), and symptomatic response (particularly sexual function) should be assessed at each visit. 5, 6
Common Pitfalls to Avoid
Do not assume that a higher-concentration formulation will produce more side effects if the total dose is equivalent. Systemic exposure, not concentration, determines patient-specific adverse effects. 2
Do not ignore secondary transfer risk. Higher-concentration formulations may reduce transfer risk by limiting the application area, but strict adherence to hand-washing, site-covering, and pre-contact washing is mandatory regardless of concentration. 1, 3
Do not apply testosterone gel to non-approved sites (e.g., scrotum, abdomen, genitals) without understanding the altered pharmacokinetics. Scrotal application produces supraphysiologic testosterone and DHT levels with much lower doses. 7, 2
Do not switch between 1% and 1.62% formulations without adjusting the dose, as they are not bioequivalent. 6, 1
Clinical Algorithm
Select the appropriate concentration based on patient preference, cost, and secondary transfer risk. Higher-concentration formulations (1.62%) may reduce transfer risk by limiting application area. 1
Prescribe the same total milligram dose regardless of concentration (e.g., 40.5 mg daily for 1.62% gel or 50 mg daily for 1% gel). 6, 1
Counsel patients on proper application technique: apply to clean, dry, intact skin of the shoulders and upper arms; wash hands immediately; cover the site with clothing after drying; wash the site before anticipated skin-to-skin contact. 1
Monitor serum testosterone at 2–3 months, targeting 450–600 ng/dL. Adjust the dose (not the concentration) if levels are suboptimal. 5, 6, 1
Monitor hematocrit, PSA, and symptomatic response every 6–12 months once stable. Withhold treatment if hematocrit exceeds 54%. 5, 6